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J. Biol. Chem., Vol. 279, Issue 48, 49579-49587, November 26, 2004

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Cardiac Troponin T Isoforms Affect the Ca²+ Sensitivity of Force Development in the Presence of Slow Skeletal Troponin I

INSIGHTS INTO THE ROLE OF TROPONIN T ISOFORMS IN THE FETAL HEART^*

Aldrin V. Gomes, Gayathri Venkatraman¶, Jonathan P. Davis||, Svetlana B. Tikunova||, Patti Engel**, R. John Solaro**, and James D. Potter

From the Department of Molecular and Cellular Pharmacology and the ^¶Department of Physiology and Biophysics, University of Miami School of Medicine, Miami, Florida 33136, the ^||Department of Physiology and Cell Biology, Ohio State University, Columbus, Ohio 43210, and the ^**Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, Illinois 60612

In this study we investigated the physiological role of the cardiac troponin T (cTnT) isoforms in the presence of human slow skeletal troponin I (ssTnI). ssTnI is the main troponin I isoform in the fetal human heart. In reconstituted fibers containing the cTnT isoforms in the presence of ssTnI, cTnT1-containing fibers showed increased Ca²⁺ sensitivity of force development compared with cTnT3- and cTnT4-containing fibers. The maximal force in reconstituted skinned fibers was significantly greater for the cTnT1 (predominant fetal cTnT isoform) when compared with cTnT3 (adult TnT isoform) in the presence of ssTnI. Troponin (Tn) complexes containing ssTnI and reconstituted with cTnT isoforms all yielded different maximal actomyosin ATPase activities. Tn complexes containing cTnT1 and cTnT4 (both fetal isoforms) had a reduced ability to inhibit actomyosin ATPase activity when compared with cTnT3 (adult isoform) in the presence of ssTnI. The rate at which Ca²⁺ was released from site II of cTnC in the cTnI·cTnC complex (122/s) was 12.5-fold faster than for the ssTnI·cTnC complex (9.8/s). Addition of cTnT3 to the cTnI·cTnC complex resulted in a 3.6-fold decrease in the Ca²⁺ dissociation rate from site II of cTnC. Addition of cTnT3 to the ssTnI·cTnC complex resulted in a 1.9-fold increase in the Ca²⁺ dissociation rate from site II of cTnC. The rate at which Ca²⁺ dissociated from site II of cTnC in Tn complexes also depended on the cTnT isoform present. However, the TnI isoforms had greater effects on the Ca²⁺ dissociation rate of site II than the cTnT isoforms. These results suggest that the different N-terminal TnT isoforms would produce distinct functional properties in the presence of ssTnI when compared with cTnI and that each isoform would have a specific physiological role in cardiac muscle.

Received for publication, June 30, 2004 , and in revised form, August 31, 2004.

^* This work was supported in part by National Institutes of Health Grants HL42325, HL67415 (to J. D. P.), AR20792 (to J. A. Rall), HL073600 (to S. B. T.), and HL 62426 (to R. J. S.) and by an award from the American Heart Association, Ohio Valley Affiliate (to J. P. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by an award from the Muscular Dystrophy Association.

Supported by an American Heart Association, Midwest Affiliate, predoctoral fellowship, and National Institutes of Health Grant T32 HL 07692.

To whom correspondence should be addressed: Dept. of Molecular and Cellular Pharmacology, University of Miami School of Medicine, 1600 N.W. 10th Ave., Miami, FL 33136. Tel.: 305-243-5874; Fax: 305-324-6024; E-mail: jdpotter{at}miami.edu.

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